A Small-Molecule Modulator Interacts Directly with ΔPhe508-CFTR to Modify Its ATPase Activity and Conformational Stability

2009 ◽  
Vol 75 (6) ◽  
pp. 1430-1438 ◽  
Author(s):  
Leigh Wellhauser ◽  
Patrick Kim Chiaw ◽  
Stan Pasyk ◽  
Canhui Li ◽  
Mohabir Ramjeesingh ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Small Molecule ◽  
Conformational Stability ◽  
Small Molecule Modulator

Direct interaction of a small-molecule modulator with G551D-CFTR, a cystic fibrosis-causing mutation associated with severe disease

2009 ◽  
Vol 418 (1) ◽  
pp. 185-190 ◽  
Author(s):  
Stan Pasyk ◽  
Canhui Li ◽  
Mohabir Ramjeesingh ◽  
Christine E. Bear
Keyword(s):  
Cystic Fibrosis ◽  
Atpase Activity ◽  
Small Molecule ◽  
Mechanism Of Action ◽  
Severe Disease ◽  
Atp Binding ◽  
Molecular Defect ◽  
Apical Surface ◽  
Channel Activity ◽  
Small Molecule Modulator

CF (cystic fibrosis) is caused by mutations in CFTR (CF transmembrane conductance regulator), which cause its mistrafficking and/or dysfunction as a regulated chloride channel on the apical surface of epithelia. CFTR is a member of the ABC (ATP-binding-cassette) superfamily of membrane proteins and a disease-causing missense mutation within the ABC signature sequence; G551D-CFTR exhibits defective phosphorylation and ATP-dependent channel gating. Studies of the purified and reconstituted G551D-CFTR protein revealed that faulty gating is associated with defective ATP binding and ATPase activity, reflecting the key role of G551 in these functions. Recently, high-throughput screens of chemical libraries led to identification of modulators that enhance channel activity of G551D-CFTR. However, the molecular target(s) for these modulators and their mechanism of action remain unclear. In the present study, we evaluated the mechanism of action of one small-molecule modulator, VRT-532, identified as a specific modulator of CF-causing mutants. First, we confirmed that VRT-532 causes a significant increase in channel activity of G551D-CFTR using a novel assay of CFTR function in inside-out membrane vesicles. Biochemical studies of purified and reconstituted G551D-CFTR revealed that potentiation of the ATPase activity of VRT-532 is mediated by enhancing the affinity of the mutant for ATP. Interestingly, VRT-532 did not affect the ATPase activity of the Wt (wild-type) CFTR, supporting the idea that this compound corrects the specific molecular defect in this mutant. To summarize, these studies provide direct evidence that this compound binds to G551D-CFTR to rescue its specific defect in ATP binding and hydrolysis.

scholarly journals A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle

2017 ◽  
Vol 292 (40) ◽  
pp. 16571-16577 ◽  
Author(s):  
Raja F. Kawas ◽  
Robert L. Anderson ◽  
Sadie R. Bartholomew Ingle ◽  
Yonghong Song ◽  
Arvinder S. Sran ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cardiac Myosin ◽  
Small Molecule Modulator ◽  
Multiple Stages

scholarly journals A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease

2019 ◽  
Vol 11 (514) ◽  
pp. eaau6870 ◽  
Author(s):  
Lena F. Burbulla ◽  
Sohee Jeon ◽  
Jianbin Zheng ◽  
Pingping Song ◽  
Richard B. Silverman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Molecule ◽  
Dopaminergic Neurons ◽  
Wild Type ◽  
Gene Encoding ◽  
Alternative Approach ◽  
Consequent Reduction ◽  
Small Molecule Modulator ◽  
Small Molecule Modulators

Mutations in the GBA1 gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson’s disease (PD). GCase has been identified as a potential therapeutic target for PD and current efforts are focused on chemical chaperones to translocate mutant GCase into lysosomes. However, for several GBA1-linked forms of PD and PD associated with mutations in LRRK2, DJ-1, and PARKIN, activating wild-type GCase represents an alternative approach. We developed a new small-molecule modulator of GCase called S-181 that increased wild-type GCase activity in iPSC-derived dopaminergic neurons from sporadic PD patients, as well as patients carrying the 84GG mutation in GBA1, or mutations in LRRK2, DJ-1, or PARKIN who had decreased GCase activity. S-181 treatment of these PD iPSC-derived dopaminergic neurons partially restored lysosomal function and lowered accumulation of oxidized dopamine, glucosylceramide and α-synuclein. Moreover, S-181 treatment of mice heterozygous for the D409V GBA1 mutation (Gba1D409V/+) resulted in activation of wild-type GCase and consequent reduction of GCase lipid substrates and α-synuclein in mouse brain tissue. Our findings point to activation of wild-type GCase by small-molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of PD that exhibit decreased GCase activity.

scholarly journals A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Kyung-Hwa Baek ◽  
Haiying Zhang ◽  
Bo Ryeong Lee ◽  
Young-Guen Kwon ◽  
Sang-Jun Ha ◽  
...  
Keyword(s):  
Immune Response ◽  
Atpase Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Protein Antigens ◽  
Molecule Inhibitor

BzDANP, a Small-Molecule Modulator of Pre-miR-29a Maturation by Dicer

2016 ◽  
Vol 11 (10) ◽  
pp. 2790-2796 ◽  
Author(s):  
Asako Murata ◽  
Takahiro Otabe ◽  
Jinhua Zhang ◽  
Kazuhiko Nakatani
Keyword(s):  
Small Molecule ◽  
Small Molecule Modulator
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